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US11291672B2 - Betamethasone oral spray formulation and method of use to treat ataxia - Google Patents

Betamethasone oral spray formulation and method of use to treat ataxia Download PDF

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US11291672B2
US11291672B2 US15/404,859 US201715404859A US11291672B2 US 11291672 B2 US11291672 B2 US 11291672B2 US 201715404859 A US201715404859 A US 201715404859A US 11291672 B2 US11291672 B2 US 11291672B2
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formulation
betamethasone
spray
glucocorticoid
stable
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US20170196889A1 (en
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S. George Kottayil
Amresh Kumar
Prasanna Sunthankar
Vimal Kavuru
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Acasti Pharma US Inc
Grace Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention is directed in part to an ambient temperature stable oral spray formulation of glucocorticoid steroid for treating neurological disorders, and in part to an oral betamethasone spray formulation for the treatment of ataxia telangiectasia.
  • Betamethasone is a glucocorticoid and belongs to a group of drugs called corticosteroids.
  • the approved indications of betamethasone include numerous steroid responsive diseases, including allergic states, dermatologic diseases, endocrine disorders, gastrointestinal diseases, hematologic disorders, parasitic conditions, rheumatic disorders, cancer, and other conditions related to the nervous system, eyes, kidneys, and lungs.
  • Betamethasone has been approved in the U.S. in multiple forms (oral solid, oral liquid, injection, and topical), both as a free base (NDAs 12657, 14215, 17561 and 14762, respectively), as an injectable in combination with betamethasone acetate (NDA 14602), and in a number of salt forms.
  • the innovator betamethasone base product was sold under the trade name Celestone® by Merck & Co./Schering (Merck) and the innovator continues to market the combination product under the trade name Celestone® Soluspan®. There is also a generic form of the combination available. Over the past years, all of the betamethasone oral product NDAs have been withdrawn (not for safety or efficacy reasons) as these products are no longer marketed.
  • Betamethasone is also available as an injectable suspension (e.g., Celestone® Soluspan® Injectable Suspension) in a strength of 3 mg/ml (equivalent to 3 mg/base/ml), which has similar indications.
  • the injectable suspension includes a combination of betamethasone acetate and betamethasone sodium phosphate as the active ingredient.
  • betamethasone is commercially available in the U.S. in a variety of forms, including aerosol, foam (e.g., in the form of betamethasone valerate); as a lotion, topical suspension, ointment or cream (e.g., in the form of betamethasone dipropionate).
  • Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension USP is a sterile aqueous suspension containing betamethasone 3 mg per milliliter as betamethasone sodium phosphate, and betamethasone acetate 3 mg per milliliter.
  • Inactive ingredients per mL dibasic sodium phosphate 7.1 mg; monobasic sodium phosphate 3.4 mg; edetate disodium 0.1 mg; and benzalkonium chloride 0.2 mg as a preservative.
  • the pH is adjusted to between 6.8 and 7.2.
  • Betamethasone sodium phosphate, a soluble ester provides prompt activity, while betamethasone acetate is only slightly soluble and affords sustained activity.
  • Such formulation is commercially available in the U.S.
  • Celestone Soluspan® from Merck Sharp and Dohme Corp.
  • Betavet® from Luitpold Pharmaceuticals, Inc.
  • a sterile aqueous suspension of betamethasone acetate in betamethasone sodium phosphate injection is a sterile aqueous suspension of betamethasone acetate in betamethasone sodium phosphate injection.
  • Celastone Soluspan is indicated for IM injection in allergic, dermatologic, rheumatic, and other conditions responsive to systemic corticosteroids, including bursitis; injection directly into the affected tissues in bursitis and associated inflammatory disorders of tendons such as tenosynovitis, and inflammatory disorders of muscle such as fibrosis and myositis; intra-articular and periarticular injection in rheumatoid arthritis and osteoarthritis; intralesional injection in various dermatologic conditions; and local injection in certain inflammatory and cystic disorders of the foot.
  • Betamethasone sodium phosphate, a soluble ester provides prompt activity, while betamethasone acetate is only slightly soluble and affords sustained activity. Betamethasone sodium phosphate injection (EQ 3 mg base/ml) was also available in the U.S. under the tradename Celastone (from Shering Corp.), but that product was discontinued.
  • Ataxia describes a lack of muscle control during voluntary movements, such as walking or picking up objects.
  • a sign of an underlying condition, ataxia can affect movement, speech, eye movement and swallowing.
  • Persistent ataxia usually results from damage to the cerebellum—a part of the brain that controls muscle coordination.
  • Many conditions can cause ataxia, including alcohol abuse, stroke, tumor, cerebral palsy and multiple sclerosis.
  • An inherited defective gene can also cause ataxia.
  • Treatment for ataxia depends on the cause.
  • Adaptive devices, such as walkers or canes, might help maintain independence. Physical therapy, occupational therapy and speech therapy also might help.
  • the cerebellum comprises two pingpong-ball-sized portions of folded tissue situated at the base of the brain near the brainstem. The right side of the cerebellum controls coordination on the right side of your body; the left side of the cerebellum controls coordination on the left.
  • the causes of ataxia include: (i) Head trauma (Damage to the brain or spinal cord from a blow to the head, such as might occur in a car accident, can cause sudden-onset ataxia, also known as acute cerebellar ataxia); (ii) Stroke (When blood supply to a part of the brain is interrupted or severely reduced depriving brain tissue of oxygen and nutrients, brain cells die); (iii) Transient ischemic attack (TIA; Caused by a temporary decrease in blood supply to part of the brain. Most TIAs last only a few minutes.
  • Cerebral palsy (This is a general term for a group of disorders caused by damage to a child's brain during early development—before, during or shortly after birth—that affects the child's ability to coordinate body movements); (v) Multiple sclerosis (MS, which is a chronic, potentially debilitating disease that affects the central nervous system; (vi) Chickenpox (Ataxia can be an uncommon complication of chickenpox and other viral infections. It may appear in the healing stages of the infection and last for days or weeks.
  • the ataxia resolves over time);
  • Paraneoplastic syndromes These are rare, degenerative disorders triggered by the immune system's response to a cancerous tumor (neoplasm), most commonly from lung, ovarian, breast or lymphatic cancer. Ataxia may appear months or years before the cancer is diagnosed);
  • Tumor A growth on the brain, cancerous (malignant) or noncancerous (benign), can damage the cerebellum);
  • Toxic reaction (Ataxia is a potential side effect of certain medications, especially barbiturates such as phenobarbital and sedatives such as benzodiazepines.
  • Vitamin E or vitamin B-12 deficiency (Not getting enough vitamin E or vitamin B-12, because of the inability to absorb enough of the vitamin or other reasons can lead to ataxia).
  • sporadic degenerative ataxia For some adults who develop sporadic ataxia, no specific cause can be found. This is known as sporadic degenerative ataxia, which can take a number of forms, including multiple system atrophy, a progressive degenerative disorder.
  • Ataxia and some conditions that cause ataxia are hereditary. This is due to a birth defect in a certain gene that makes abnormal proteins. The abnormal proteins hamper the function of nerve cells, primarily in the cerebellum and spinal cord and cause them to degenerate. As the disease progresses, coordination problems worsen.
  • Episodic ataxia There are seven recognized types of ataxia that are episodic rather than progressive—EA1 through EA7. EA1 and EA2 are the most common. EA1 involves brief ataxic episodes that may last seconds or minutes. The episodes are triggered by stress, being startled or sudden movement, and often are associated with muscle twitching. EA2 involves longer episodes, usually lasting from 30 minutes to six hours, that also are triggered by stress. With this type of ataxia, you may experience dizziness (vertigo), fatigue and muscle weakness during your episodes. In some cases of episodic ataxia, symptoms resolve in later life. Episodic ataxia doesn't shorten life span, and symptoms may respond to medication.
  • Friedreich's ataxia This, the most common hereditary ataxia, involves damage to your cerebellum, spinal cord and peripheral nerves. Peripheral nerves carry signals from your brain and spinal cord to your muscles. In most cases, signs and symptoms appear before the age of 25. The rate of disease progression varies.
  • the first indication generally is difficulty walking (gait ataxia). The condition typically progresses to the arms and trunk. Muscles weaken and waste away over time, causing deformities, particularly in your feet, lower legs and hands.
  • AT Ataxia-telangiectasia
  • the disease causes immune system breakdown (immunodeficiency disease), which increases susceptibility to other diseases. It affects various organs.
  • AT is a rare genetic progressive autosomal recessive neurodegenerative disorder that affects children, with the hallmark symptoms of cerebellar ataxia and other motor dysfunction, and dilated blood vessels (telangiectasia) that occur in the sclera of the eyes.
  • AT is caused by mutations in the ATM (ataxia telangiectasia mutated) gene, which is responsible for modulating cellular response to stress, including breaks in the double strands of DNA.
  • Telangiectasias are tiny red “spider” veins that may appear in the corners of the child's eyes or on the ears and cheeks. Although characteristic of the disease, some children may not develop telangiectasias. Children begin to experience balance and coordination problems when they begin to walk (toddler age), and ultimately become wheelchair bound in their second decade of life. In pre-adolescence (age 5-8), patients experience oculomotor apraxia, dysarthria, and dysphagia. They also often develop compromised immune systems, and are at increased risk of developing respiratory tract infections and cancer (typically lymphomas and leukemia). Delayed motor skill development, poor balance and slurred speech are typically the first indications of the disease. Recurrent sinus and respiratory infections are common.
  • AT is diagnosed through a combination of clinical assessment (especially neurologic and oculomotor deficits), laboratory analysis, and genetic testing. There is no known treatment to slow disease progression, and treatments that are used are strictly aimed at symptoms (e.g. physical, occupational or speech therapy for neurologic issues), or conditions secondary to the disease (e.g. antibiotics for lung infections, chemotherapy for cancer, etc.). Patients typically die by age 25 from complications of lung disease or cancer.
  • Buoni et al (Betamethasone and improvement of neurological symptoms in ataxia telangiectasia. Arch Neurol 2006; 63: 1469-82) observed improvements in the neurological symptoms of a 3-year-old boy with the classic hallmarks, and a proven molecular diagnosis of AT within 2-3 days of administration of betamethasone (0.1 mg/kg/day). After 4 weeks of treatment, the improvement was dramatic: the disturbance of stance and gait was clearly reduced, the control of the head and neck and of skilled movements had increased, and the neurological improvement was so great that the child was able to go up and down stairs.
  • Broccoletti et al Steroid-induced improvement of neurological signs in ataxia-telangiectasia patients. Eur J Neurol 2008; 15: 223-8
  • betamethasone 0.1 mg/kg/day
  • the neurological evaluation was performed through the Scale for the Assessment and Rating of Ataxia (SARA).
  • SARA Scale for the Assessment and Rating of Ataxia
  • glucocorticoids in general exert their remarkable effects through both genomic and nongenomic mechanisms (Stahn, et al., Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol 2007; 275: 71-78; Bruscoli et al., Genomic and non-genomic effects of different glucocorticoids on mouse thymocyte apoptosis. Eur J Pharmacol 2006; 529: 63-70).
  • the mechanism by which glucocorticoids, and betamethasone in particular, can alleviate the neurological symptoms associated with AT is not clear and is the subject of much speculation.
  • betamethasone could interact with specific receptor proteins in target tissues that regulate the expression of corticosteroid-responsive genes, prevent or suppress inflammation, enhance antioxidative pathways, enhance glucocorticoid receptors, or modulate synaptic plasticity (Buoni, 2006; Gatti et al. A proposed bailout for A-T patients? Eur J Neurol 2009; 16(6): 653-655; Zannolli et al., A randomized trial of oral betamethasone to reduce ataxia symptoms in Ataxia Telangiectasia.
  • Russo et al In ataxia-teleangiectasia betamethasone response is inversely correlated to cerebellar atrophy and directly to antioxidative capacity.
  • Russo et al evaluated intracellular GSH levels, lipid peroxidation levels and reactive oxygen species (ROS) production in six AT patients (5-29 y) treated with oral betamethasone (0.1 mg/kg/day) for 10 days, and compared those parameters with the improvement of cerebellar functions expressed as delta (D) of the SARA score. They observed an inverse correlation between D SARA and the severity of cerebellar atrophy and between the latter and basal GSH values.
  • ROS reactive oxygen species
  • the voxel-based comparison showed a remarkable increase in the number of activated voxels within the motor cortex under the on-therapy condition as compared with the cortical activity under baseline condition in the 2 patients who completed the study protocol, thus suggesting that steroid treatment could improve motor performance facilitating cortical compensatory mechanisms in AT patients.
  • Zannolli et al studied the effect of betamethasone on the reduction of ataxia symptoms in 13 children (2-8 y) with AT (Zannolli et al., A randomized trial of oral betamethasone to reduce ataxia symptoms in Ataxia Telangiectasia. Mov Dis 2012; 27: 1312-16).
  • Patients were randomly assigned to first receive either betamethasone or placebo at a dose of 0.1 mg/kg/day for 30 days: at full dose for the first 10 days, at a tapered dose on days 11-20 (i.e., for 4 days, 0.075 mg/kg/day; for 4 days, 0.050 mg/kg/day; and for 2 days, 0.025 mg/kg/day); and at full dose for the last 10 days (the full dose was tapered in the middle of the treatment phase to reduce risk from potential functional suppression of the hypothalamus-hypophysis-adrenal axis).
  • Each phase of the trial was followed by a washout period of 30 days.
  • the primary outcome measure was the reduction in ataxia symptoms as assessed by the International Cooperative Ataxia Rating Scale (ICARS).
  • ICARS International Cooperative Ataxia Rating Scale
  • Betamethasone reduced the ICARS total score by a median of 13 points in the intent-to-treat (ITT) population and 16 points in the per-protocol (PP) population (i.e., median percent decreases of ataxia symptoms of 28% and 31%, respectively).
  • ITT intent-to-treat
  • PP per-protocol
  • Adverse events in the trial were minimal, with no compulsory withdrawals and only minor side effects that did not require medical intervention. Small increases in body weight were observed in 12 patients on betamethasone and in 4 patients on placebo. Moon face was present in 8 patients on betamethasone.
  • This miniATM variant was also highlighted in lymphoblastoid cell lines from AT patients and was shown to be likely active. Menotta et al concluded that induction of a truncated protein retaining kinase activity could represent one of the mechanisms by which the drug acts in treated AT patients.
  • betamethasone studies have highlighted that during the clinical course of the disease there is a phase when neurological impairment may be rescued to some extent (Giardino et al., Betamethasone therapy in ataxia telangiectasia: unraveling the rationale of this serendipitous observation on the basis of the pathogenesis. European Journal of Neurology 2013, 20: 740-747).
  • Another related disease is congenital cerebellar ataxia. This type of ataxia results from damage to the cerebellum that is present at birth.
  • Wilson's disease People with this condition accumulate copper in their brains, livers and other organs, which can cause neurological problems, including ataxia.
  • Ataxia There is no specific treatment for ataxia. In some cases, treating the underlying cause resolves the ataxia. In other cases, such as ataxia that results from chickenpox or other viral infection, it's likely to resolve on its own over time.
  • a stable liquid glucocorticoid formulation comprising a glucocorticoid consisting of (i) a disodium salt of a glucocorticoid selected from the group consisting of betamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone and triamcinolone, and mixtures of any of the foregoing and (ii) less than 11% of a glucocorticoid base selected from (i) in its base form (i.e., whichever glucocorticoid(s) is selected from the group consisting of betamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone, triamcinolone, and mixtures of any of the foregoing), in a pharmaceutically acceptable aqueous solvent (e.g, water).
  • a pharmaceutically acceptable aqueous solvent e.g, water
  • the formulation further optionally comprises a preservative, a buffering and/or pH-modifying agent, a sweetening agent and other optional pharmaceutical excipients.
  • the liquid formulation is clear and is without precipitate (i.e., does not include particulate matter such as precipitate of glucocorticoid).
  • the liquid formulation does not include a significant amount of precipitate (e.g., contains less than about 11% and most preferably less than about 10% glucocorticoid in its base form).
  • the pH of the liquid formulation is from about pH 2 to about pH 8.
  • the liquid formulation is an oral spray formulation which contains the disodium phosphate salt of the glucocorticoid in a concentration from about 0.25 to about 12 mg/ml, and provides a therapeutically effective dose in from about 1 to about 3 sprays.
  • the concentration of glucocorticoid in the aqueous liquid formulation is from about 2.35 mg/ml to about 12 mg/ml, based on the glucocorticoid in its disodium salt form.
  • the concentration of glucocorticoid in the aqueous liquid formulation is from about 3.57 mg/ml to about 8.93 mg/ml, and in other embodiments from about 7.14 mg/ml to about 8.93 mg/ml, based on the glucocorticoid in its base form.
  • the glucocorticoid consists of betamethasone.
  • the liquid formulation comprises a plurality of spray droplets, each spray providing a liquid volume from about 0.040 ml to about 0.350 ml, and most preferably in certain embodiments a liquid volume of about 0.14 ml.
  • each spray of the liquid formulation provides a glucocorticoid dose from about 0.33 mg to about 1.65 mg (based on 0.14 ml spray volume).
  • at least 90% of the liquid droplet size is more than 10 microns in order to prevent the inhalation of glucocorticoid into the lungs.
  • the liquid formulation is clear and without precipitate for at least about 24 months when stored at a temperature from about 2° C. to about 25° C.
  • the concentrations provided above will change slightly depending on the molecular weight of the respective glucocorticoid base.
  • the concentration ratio between the base and disodium phosphate for the glucocorticoids mentioned above varies between 1.28-1.34.
  • the concentrations set forth above are based on betamethasone.
  • the glucocorticoid consists of betamethasone.
  • the formulation comprises a supersaturated concentration of the drug (glucocorticoid).
  • the disodium salt of the glucocorticoid is a disodium phosphate salt.
  • the liquid formulation further includes (optional) pharmaceutically acceptable excipients, including but not limited to buffering or pH-adjusting agents, preservatives, and (water-soluble) sweeteners.
  • the stable oral spray formulation is stored at room temperature. In other embodiments, the stable oral spray formulation is stored at a temperature from about 2° C. to about 25° C. In certain preferred embodiments, the formulation is stored at a temperature from about 2° C. to about 8° C. In certain preferred embodiments, the stable oral spray formulation has a shelf life of at least about 24 months, and in certain embodiments up to about 36 months.
  • the invention is also directed in part to a stable oral spray formulation of betamethasone, consisting of a (solubilized) disodium salt of betamethasone in an aqueous solvent in a concentration from about 0.25 mg/ml to about 12 mg/ml, and in further embodiments from about 2.357 mg/ml to about 9.429 mg/ml, the oral spray formulation containing less than 10% betamethasone in base form.
  • the stable oral spray formulation comprises a unit dose of liquid droplets of the formulation, wherein each spray comprises a liquid volume of from about 0.040 ml to about 0.350 ml, and preferably about 0.14 ml.
  • the disodium salt of betamethasone is the disodium phosphate betamethasone salt.
  • not more than about 10% of the liquid droplets have a diameter less than 10 microns.
  • the liquid droplets preferably have a size distribution of from about 5 microns to about 500 microns.
  • the solvent does not include any organic solvent(s).
  • the concentration of betamethasone in the aqueous liquid formulation is from about 2.35 mg/ml to about 12 mg/ml, based on the glucocorticoid in its disodium salt form.
  • the concentration of betamethasone in the aqueous liquid formulation is from about 3.57 mg/ml to about 8.93 mg/ml, and in other embodiments from about 7.14 mg/ml to about 8.93 mg/ml, based on betamethasone in its base form.
  • each spray of the stable oral spray formulation contains the sodium salt of betamethasone in a concentration from about 0.33 mg/0.14 ml to about 1.32 mg/0.14 ml.
  • the stable oral spray formulation is supersaturated, i.e., contains the disodium phosphate salt of betamethasone in solution in an amount of about 1.65 mg dissolved in 0.14 ml (about 11.786 or 12 mg/ml).
  • the liquid formulation is clear and is without precipitate (i.e., does not include particulate matter such as precipitate of betamethasone base). In other embodiments, the liquid formulation does not include a significant amount of precipitate (e.g., contains about 11% or less, and most preferably less than about 10% betamethasone base).
  • the pH of the liquid formulation is from about pH 2 to about pH 8.
  • the concentration of the stable oral spray formulation is from about 2.35 to about 11.79 mg/ml (e.g., from about 1.78 mg/ml to about 8.93 mg/ml EQ to betamethasone base). In certain embodiments, the stable oral spray formulation is stored at room temperature.
  • the stable oral spray formulation is stored at a temperature from about 2° C. to about 25° C. In certain preferred embodiments, the formulation is stored at a temperature from about 2° C. to about 8° C. In certain preferred embodiments, the stable oral spray formulation has a shelf life of at least about 24 months, and in certain embodiments up to about 36 months.
  • the invention relates in part to an oral formulation comprising a glucocorticoid steroid, a pharmaceutically acceptable buffering agent in an amount sufficient to provide the formulation with a pH from about 2 to about 8, in a pharmaceutically acceptable solvent.
  • the formulation further comprises effective amounts of a pharmaceutically acceptable preservative, a pharmaceutically acceptable sweetener, and other pharmaceutical excipients.
  • the invention relates in part to an oral spray formulation, comprising betamethasone sodium phosphate in a pharmaceutically acceptable solvent for oral administration to humans, the concentration of the betamethasone in solution being from about 0.25 mg to about 12 mg per mL of the oral spray formulation, the oral spray formulation further optionally comprising a preservative, a buffering agent, a sweetening agent and other optional pharmaceutical excipients.
  • the concentration of the betamethasone in solution is from about 1.78 to about 8.93 mg/ml, or from about 3.57 to about 8.93 mg/ml. or from about 7.14 to about 8.93 mg/ml based on the betamethasone in its base form.
  • the stable oral spray formulation is stored at room temperature.
  • the stable oral spray formulation is stored at a temperature from about 2° C. to about 25° C. In certain preferred embodiments, the formulation is stored at a temperature from about 2° C. to about 8° C. In certain preferred embodiments, the stable oral spray formulation has a shelf life of at least about 24 months, and in certain embodiments up to about 36 months.
  • the invention is further directed in part to a stable oral spray formulation of betamethasone, consisting of a (solubilized) disodium phosphate salt of betamethasone in an aqueous solvent in a concentration from about 0.33 mg/spray to about 10 mg/spray, wherein each spray is about 0.14 ml, the stable oral spray formulation being maintained during storage at a temperature from about 2° C. to about 8° C., and the formulation being stable over its entire shelf life of at least 24 months.
  • not more than about 10% of the liquid droplets have a diameter less than 10 microns.
  • the liquid droplets preferably have a size distribution of from about 5 microns to about 500 microns.
  • the solvent does not include any organic solvent(s).
  • the concentration of betamethasone in the aqueous liquid formulation is from about up to about 71.4 mg/ml based on the glucocorticoid in its disodium salt form. In certain further preferred embodiments, the concentration of betamethasone in the aqueous liquid formulation is up to about 54.09 mg/ml based on betamethasone in its base form.
  • the stable oral spray formulation is supersaturated. In further embodiments, the stable oral spray formulation contains the disodium phosphate salt of betamethasone in solution in an amount of up to about 10 mg dissolved in 0.14 ml (up to about 71.4).
  • the liquid formulation is clear and is without precipitate (i.e., does not include particulate matter such as precipitate of betamethasone base). In other embodiments, the liquid formulation does not include a significant amount of precipitate (e.g., contains about 11% or less betamethasone base, and most preferably less than about 10% betamethasone base).
  • the pH of the liquid formulation is from about pH 2 to about pH 8.
  • the stable oral spray formulation is a supersaturated solution, meaning that the formulation will remain as a clear solution during storage up to the shelf life of drug product (e.g., at least about 24 months, and up to about 36 months in certain embodiments. The stable oral spray formulation solution reaches a supersaturated state at the end of product shelf life when stored at room temperature.
  • the oral formulations of the invention can be in the form of syrup, an aqueous solution, suspension, or oral drops.
  • the oral formulation can be in the form of a reconstituted powder in an aqueous solution that contains a buffer to regulate the pH of the solution.
  • the glucocorticoid is betamethasone and/or dexamethasone and/or prednisolone, in their base form or pharmaceutical acceptable salts, most preferably in the form of their (di)sodium phosphate salts.
  • the formulation is a sprayable formulation, preferably a metered dose oral spray which can be sprayed in the oral cavity of a human patient, e.g., over the tongue.
  • delivered spray is a plume or a stream over the tongue.
  • the present invention is also directed to a method for treating and/or preventing neurological disorder in a subject (e.g., mammal, preferably human) who has difficulty in swallowing by administering to said patient a pharmaceutically effective amount of glucocorticoid steroid, in an oral liquid formulation that can be sprayed over the tongue.
  • a subject e.g., mammal, preferably human
  • glucocorticoid steroid in an oral liquid formulation that can be sprayed over the tongue.
  • the invention is directed to a method of treating a neurological disorder in a human patient comprising orally administering a stable oral liquid formulation of a solubilized disodium salt of a glucocorticoid consisting of (i) a disodium salt of a glucocorticoid selected from the group consisting of betamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone and triamcinolone, and mixtures of any of the foregoing and (ii) about 11% or less of a glucocorticoid base selected from the group consisting of betamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone, triamcinolone, and mixtures of any of the foregoing, by spraying a unit dose of the glucocorticoid over the tongue of the human patient, the stable oral liquid formulation having a concentration of the dis
  • the concentration of the solubilized glucocorticoid is preferably from about 0.33 mg/0.14 ml to about 1.32 mg/0.14 ml.
  • the stable oral spray formulation is supersaturated.
  • Supersaturated solution for the purposes of the present invention means that the formulation will remains in the clear solution during storage at 25° C. up to the shelf life of drug product (e.g., at least 24 months, or up to about 36 months).
  • the aqueous liquid (solution) reaches its supersaturated state at the end of product shelf life when stored at room temperature.
  • the stable oral liquid formulation further comprises a pharmaceutically acceptable non-organic solvent, such as water.
  • the liquid formulation is clear and is without precipitate (i.e., does not include particulate matter such as precipitate of glucocorticoid base). In preferred embodiments, the liquid formulation does not include a significant amount of precipitate (e.g., contains less than about 11% and preferably less than about 10% glucocorticoid base).
  • the glucocorticoid salt consists of the disodium phosphate salt of betamethasone. In certain preferred embodiments, at least 90% of the liquid droplet size is more than 10 microns in order to prevent the inhalation of glucocorticoid into the lungs.
  • the liquid droplets preferably have a size distribution of from about 5 microns to about 500 microns.
  • the neurological disorder is ataxia. In certain preferred embodiments, the neurological disorder is ataxia telangiectasia. In certain embodiments, the human patient is a pediatric patient. In preferred embodiments, the glucocorticoid is betamethasone.
  • the invention is also directed in part to a method for treating a neurological disorder with an oral glucocorticoid, comprising orally administering to a human patient a stable oral liquid formulation of a solubilized disodium salt of a glucocorticoid consisting of (i) a disodium salt of a glucocorticoid selected from the group consisting of betamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone and triamcinolone, and mixtures of any of the foregoing and (ii) less than 11% of the corresponding base form of the glucocorticoid, in water, by spraying a unit dose of the glucocorticoid over the tongue of the human patient, the stable oral liquid formulation having a concentration of the disodium salt of the glucocorticoid from about 0.25 mg/ml to about 12 mg/ml, wherein each spray has a liquid volume from about
  • the invention is also directed in part to a method for treating a neurological disorder, comprising orally administering to a human patient a stable oral liquid spray formulation of a solubilized disodium phosphate salt of betamethasone in water by spraying a unit dose of the solubilized disodium phosphate salt of betamethasone into the oral cavity of a human patient, wherein the unit dose comprises from 1 to about 7 sprays of the stable oral liquid formulation and the concentration of the disodium phosphate salt of betamethasone in the formulation is from about 3.57 mg/ml to about 8.93 mg/ml EQ to betamethasone base and the stable oral liquid spray formulation is clear and without precipitate.
  • the oral spray of the glucocorticoid (e.g., betamethasone) is delivered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 19 or 20 sprays.
  • a unit dose of the oral spray is delivered in from about 1 to about 7 sprays (e.g., of a mechanically actuated oral spray device).
  • the concentration of disodium salt of the glucocorticoid in the oral spray formulation is about 0.25 mg/0.14 ml, 0.26 mg/0.14 ml, 0.27 mg/0.14 ml, 0.28 mg/0.14 ml, 0.29 mg/0.14 ml, 0.30 mg/0.14 ml, 0.31 mg/0.14 ml, 0.32 mg/0.14 ml, 0.33 mg/0.14 ml, 0.34 mg/0.14 ml or 0.35 mg/0.14 ml, 0.36 mg/0.14 ml, 0.37 mg/0.14 ml, 0.38 mg/0.14 ml, 0.39 mg/0.14 ml, 0.40 mg/0.14 ml, 0.41 mg/0.14 ml, 0.42 mg/0.14 ml, 0.43 mg/0.14 ml, 0.44 mg/0.14 ml, 0.45 mg/0.14 ml, 0.46 mg/0.14 ml, 0.47 mg/0.1
  • the liquid pharmaceutical composition of this invention preferably contains a pharmaceutically effective amount of a soluble salt of a glucocorticoid steroid (e.g., a disodium salt of betamethasone and/or dexamethasone and/or hydrocortisone, and/or triamcinolone and/or prednisolone and/or methylprednisolone) in a pharmaceutically acceptable liquid carrier e.g. purified water, and a buffer, e.g. citrate, to maintain the pH at from about 2 to about 8 and preferably at a pH from about 3 to about 6.
  • the formulation may also include an optional complexing agent, e.g. citrate or EDTA, to inhibit the precipitation of drug substance from the aqueous medium.
  • the liquid formulation of the invention is an aqueous solution that contains a high concentration of sugar or sugar substitute (e.g., sorbitol) thus providing for a syrup, which can be flavored for marketing desirability.
  • sugar or sugar substitute e.g., sorbitol
  • the amount of sugar or sugar substitute is from about 5 to about 90%, by weight.
  • the stable liquid formulation of the invention is an oral syrup or an oral suspension.
  • the liquid formulation of the invention is an injectable formulation, wherein the pharmaceutically acceptable solvent comprises water for injection.
  • composition comprising a powder for reconstitution containing a pharmaceutically effective amount of glucocorticoid steroid in particular betamethasone and/or dexamethasone in a pharmaceutically acceptable dry (solid) excipient also in the presence of a buffer, e.g. citrate, and complexing agent, said powder capable of dissolving in water.
  • a buffer e.g. citrate, and complexing agent
  • compositions comprising an oral spray over the tongue containing a pharmaceutically effective amount of glucocorticoid steroid in particular betamethasone and/or dexamethasone in a pharmaceutically acceptable excipient also in the presence of a buffer, e.g. citrate and/or complexing agent.
  • a buffer e.g. citrate and/or complexing agent.
  • the invention is also directed in part to a method of treating a neurological disorder comprising administering the liquid formulation of the present invention to a subject (e.g., human patient).
  • a subject e.g., human patient
  • the liquid formulation is sprayed into the oral cavity (e.g., over the tongue) of the patient in the form of liquid droplets.
  • the liquid droplets preferably have a size distribution of from about 5 microns to about 500 microns.
  • the invention is further directed in part to a method for treating a neurological disorder, comprising preparing a non-propellant based betamethasone oral liquid spray formulation having a concentration of solubilized betamethasone from about 0.25 mg to about 1 mg per 0.14 mL of the oral spray formulation, storing the glucocorticoid formulation in a metered dose mechanical spray pump device, and administering a therapeutically effective dose of said glucocorticoid into the oral cavity of a patient in need thereof by spraying from about 1 to about 5 spray actuations of the mechanical spray pump, wherein each spray actuation delivers about 0.14 mL of the oral spray formulation.
  • the oral spray droplet size of 90% of the liquid particles (Dv(90)) is 131 ⁇ m ⁇ 30.
  • the dose of betamethasone is titrated until steady-state is achieved.
  • the dose of the oral betamethasone spray formulation during a titration phase is from about 0.01 to about 0.2 mg/kg patient body weight administered once over a 12 hour and or 24 hour period. This translates to a betamethasone dose from about 0.07 mg to about 28 mg total per day, based on an average adult weighing 70 kg (based on betamethasone base).
  • the betamethasone dose may be from about 0.07 mg to about 14 mg for once daily dosing (every 24 hours) and from about 0.14 mg to about 28 mg for twice-a-day dosing (every 12 hours), based on an average adult weighing 70 kg (based on betamethasone base).
  • the titration period may be, e.g., from about 2 to about 4 weeks, until steady-state is achieved.
  • the dose can be further titrated based on the individual patient response.
  • the dose of the oral betamethasone spray formulation at steady-state in such embodiments is preferably from about 0.02 to about 0.1 mg/kg patient body weight administered once over a 12 hour and or 24 hour period.
  • the invention is further directed in part to a method of treating a human patient with an oral betamethasone formulation, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a propellant-free oral betamethasone spray formulation having a concentration of solubilized betamethasone from about 0.25 mg to about 1 mg per 0.14 mL of the oral spray formulation.
  • the invention is further directed in part to a method of treating a neurological disorder in a human, comprising orally administering to a human patient in need thereof a therapeutically effective dose of a propellant-free oral betamethasone spray formulation contained in a metered dose mechanical spray pump device which provides liquid particles which have a Dv(90) of about 131 ⁇ m ⁇ 30 when the device is actuated, wherein the therapeutically effective dose is administered in from 1 to about 10 actuations.
  • the concentration of solubilized betamethasone in the oral betamethasone spray formulation is from about 0.25 mg to about 1 mg per 0.14 mL, or to about 1.32 mg per 0.14 ml.
  • the invention is further directed in part to a method of treating a neurological disorder in a human, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a propellant-free oral betamethasone spray formulation having a concentration of solubilized betamethasone from about 0.25 mg to about 1 mg per 0.14 mL of the oral spray formulation.
  • the dose administered is from about 0.25 mg to about 4 mg over a 12 hour period.
  • the oral spray formulation of the invention is lyophilized, and the method further comprises reconstituting the spray formulation from a dry state by admixing with a suitable solvent(s) prior to administration.
  • the aqueous formulation of the present invention is stable for at least 6 months, preferably 12 months, more preferably 24 months, and even preferably 36 months at room temperature.
  • the conversion to betamethasone base during storage at about 25° C. should not be more than 15% of total betamethasone in the formulation, and even preferably not more than 10% of total betamethasone in the formulation.
  • the oral spray formulation provides a maximum mean plasma concentration of betamethasone about 190 ng/ml in-vivo after an oral application of 0.1 mg/kg/day betamethasone.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • unit dose refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing as the active ingredient a predetermined quantity of the active agent (e.g., glucocorticoid steroid).
  • active agent e.g., glucocorticoid steroid
  • a “therapeutically effective amount” means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
  • treating or “treatment” of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
  • a “disease” includes neurological disorders.
  • the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group that preferably consists of these embodiments only.
  • the term “consisting of” means “including and limited to”.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • FIG. 1 is a graph depicting the average droplet size distribution plot of Example 1.
  • FIG. 2 is a graph depicting the percentage betamethasone base conversion when formulation stored at different temperatures for Example 7.
  • FIG. 3 is a graph depicting mean plasma concentration-time profile of betamethasone following reference (oral solution) and oral spray of the invention (Example 3) oral route of administration in rabbits.
  • FIG. 4 is a graph depicting a prediction of betamethasone base conversion over time at 25° C. for Examples 1, 2 and 3.
  • FIG. 5 is a graph depicting a prediction of betamethasone base conversion over time at 25° C. at higher drug concentrations.
  • Corticosteroids such as betamethasone, dexamethasone, and prednisolone are anti-inflammatory drugs; they are often available as the corresponding 21-phosphate esters that are formulated into various dosage forms due to their much-enhanced solubility in an aqueous environment. Yet, the introduction of the phosphate group at the 21-hydroxyl of the steroid core structures might impart additional degradation pathways to the resulting hydrolysis and conversion to betamethasone base, which will precipitate out from the solution at higher temperature during storage. In the solid state it is only stable when stored in tightly closed container at a temperature from 2° C. to 8° C. For example, the stability of betamethasone sodium phosphate is very low in aqueous solution and strongly influenced by storage temperature.
  • betamethasone sodium phosphate is C 22 H 28 FN a2 O 8 P and it has a molecular weight of 516.41. Chemically, it is 9-Fluoro-11 ⁇ ,17,21-trihydroxy-16 ⁇ -methylpregna-1,4-diene-3,20-dione 21-(disodium phosphate).
  • the aqueous formulation of the present invention is stable for at least 6 months, preferably 12 months, more preferably 24 months, and even preferably 36 months.
  • “Aqueous formulation of the present invention is stable” means that after 6, 12, 24 or 36 months at a selected temperature (preferably at about 25° C.) the amount of the sodium salt (e.g., disodium phosphate salt) of the soluble glucocorticoid (e.g., betamethasone) present in the aqueous formulation of the present invention is reduced by a maximum of 10%, and preferably by a maximum of 8%, compared to the amount present initially after preparation of the aqueous formulation, preferably after filtration step if any.
  • the aqueous formulation of the present invention is stable for at least 24 months, and even preferably 36 months.
  • the liquid formulation does not contain any precipitation (it is a clear solution).
  • betamethasone base precipitates out from the formulation because of poor aqueous solubility. This is not acceptable for a stable formulation.
  • stable means that the conversion of the disodium phosphate salt of the glucocorticoid(s) to glucocorticoid base (e.g., disodium phosphate salt of betamethasone to betamethasone base) during storage at about 25° C.
  • the betamethasone base precipitates out in the oral spray formulation when it converts to more than 0.15 mg/0.14 ml (spray volume) (equivalent to 1.07 mg/ml).
  • the stability of the glucocorticoid (e.g., betamethasone) in the formulation can be improved by storing the formulation of the invention at temperature below 10° C., and in certain embodiments preferably between about 2° C. and about 8° C.
  • Oral solutions of glucocorticoid steroid in the form of an oral spray, drop, syrup, an aqueous solution, or a reconstituted aqueous solution of a powder offer the advantages of ease of administration, increased compliance for patients who have difficulty swallowing solid oral dosage forms and/or large volumes of liquid formulation.
  • An oral spray formulation also offers the additional advantage of minimizing storage space in nursing homes, pharmacies, hospitals and warehouses. These formulations have the advantage of permitting dose titration should this be desired based on the patient weight.
  • an oral spray can be prepared, for example, by adding the drug, buffering agent, preservatives and sweetening agent to the solvent while stirring the solution to ensure complete dissolution of the drug and excipients.
  • Aqueous or hydro alcoholic solvents can be utilized for the liquid formulations of the invention.
  • the formulations can be stored, e.g., in glass vials sealed tightly with a cap or spray pump.
  • the formulation of the invention is a multi-dose and or unit dose of a glucocorticoid (e.g., betamethasone) oral spray formulation, this formulation comprising liquid droplets of glucocorticoid, a pharmaceutically acceptable salt thereof, or derivative thereof; and a pharmaceutically acceptable solvent carrier.
  • a glucocorticoid e.g., betamethasone
  • the liquid droplets preferably have a size distribution of from about 5 microns to about 500 microns.
  • glucocorticoid in water-soluble form can be used in the formulations of the invention.
  • Representative examples include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide
  • Betamethasone, dexamethasone, triamcinolone, prednisolone, methylprednisolone and hydrocortisone are preferred, and their disodium phosphate salts are especially preferred.
  • a portion of the glucocorticoid(s) may be in base form, but it is preferred that the amount of glucocorticoid base is limited such that the base does not precipitate out of the solvent (e.g., water).
  • the glucocorticoid may be in the form of other (water-soluble) pharmaceutically acceptable salts or complexes.
  • the liquid formulations of the invention include a pH modifying agent and/or a buffer in order to adjust the pH of the liquid to a pH from about 2 to about 8, and in certain preferred embodiments to a pH from about 3 to about 7.
  • pH modifying agents e.g., alkalizing agents
  • alkalizing agents include but are not limited to NaOH, KOH, triethylamine, meglumine, L-Arginine, sodium bicarbonate, and mixtures of any of the foregoing.
  • pH modifying agents include, for example, but are not limited to, one or more adipic acids, glycines, citric acids, lactic acid, hydrochloric acid, calcium hydroxides, magnesium aluminometasilicates, and or any combinations thereof.
  • Examples of pharmaceutically acceptable buffers include but are not limited to sodium phosphate buffer (either sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, or o-phosphoric acid), potassium phosphate buffers, and the like.
  • the formulation further comprises a pharmaceutically acceptable complexing agent.
  • the complexing agent is preferably included in an amount sufficient to inhibit the precipitation of drug substance (e.g., glucocorticoid) from the solvent (e.g., aqueous medium).
  • drug substance e.g., glucocorticoid
  • solvent e.g., aqueous medium.
  • Complexing agents are small molecular weight molecules which can form an inclusion complex and after suitable curing time, can solubilize the drug and may impart additional stability to the drug. Accordingly, for purposes of the present invention, the term “complexing agent” is meant to encompass agents that complex and/or solubilize a water-insoluble statin.
  • the pharmaceutically acceptable complexing agent is a dextrin.
  • Suitable dextrins include cyclodextrins such as hydroxy-propyl- ⁇ -cyclodextrin and sulfobutyl-ether- ⁇ -cyclodextrin. Additional cyclodextrins could include alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, beta-cyclodextrin ether comprising one or more hydroxybutyl sulfonate moieties and cyclodextrins as described in U.S. Pat. Nos. 6,610,671 or 6,566,347 (both of which are incorporated by reference).
  • Additional complexing agents include, but are not limited to, the group consisting of phenol, phenolic salts, aromatic acids and esters, carboxylic acids and salts and esters thereof, inorganic acids and bases and amino acids and esters and salts thereof: methylparaben, propylparaben, potassium methylparaben, parabens, ascorbic acid and its derivatives, methyl anthranilate, salicylic acid, acetosalicyclic acid, tocopherol, organic acids, carboxylic acids, aromatic acids, aromatic esters, acid salts of amino acids, benzaldehyde, cinnimaldehyde, imidazole, menthol, thiophenol, m-aminobenzoic acid, anthranilic acid, picolinic acids and alkyl esters thereof, toluidides, sodium benzoate, sodium metabisulphite, malic acid, isoascorbic acid, citric acid, tartaric acid, sodium sulphite, sodium bis
  • the complexing agent comprises at least 0.1% of the formulation. In other preferred embodiments, the complexing agent comprises from about 0.05 to about 50% of the formulation, by weight. In certain preferred embodiments, the complexing agent is included in the solid formulation prior to reconstitution.
  • the liquid dosage forms of the invention for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and the like.
  • the formulation of the invention includes one or preservatives, e.g., more antimicrobial agents in bacteriostatic or fungistatic concentrations. Typically, such agents are added where the formulation is packaged in multiple dose containers.
  • pharmaceutically acceptable antimicrobial agents include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride, chlorinated phenolic compounds, alcohols, quaternary compounds, boric acid, benzoic acid, sodium benzoate and mixtures of any of the foregoing.
  • the liquid formulation further comprises one or more suspending and dispersing agents.
  • suitable agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
  • Emulsifying agents include Polysorbate 80 (TWEEN® 80).
  • the liquid formulation preferably includes or consists of an aqueous carrier (e.g., water), although in certain embodiments the carrier may comprise a hydroalcoholic carrier.
  • aqueous carrier e.g., water
  • pharmaceutical carriers also include, by way of example and without limitation, ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles.
  • the solvent concentration is from about 20 to about 99%, by weight.
  • the liquid formulation is lyophilized for later reconstitution prior to administration.
  • the formulation can be prepared as a dry pre-mix powder.
  • the lyophilized particles comprising the glucocorticoid are stable.
  • stable it is meant that substantially no degradation of the dry mix and or lyophilized particles (the product) is observed after storage for 1 month at 40° C.
  • the term “stable” with respect to the dry mix and or lyophilized particles comprising the water-insoluble statin and complexing agent means that there is less than about 0.1% degradation observed) after storage for 1 month at 40° C.
  • optimal viscosities of the system of the invention will range from about 0.25 to about 200,000 centipoise, preferably from about 0.3 to 1000 centipoise, and more preferably from about 0.5 to about 100 centipoise, at 37° C. While the benefit of the invention is realized over a broad range of elevated viscosities, the optimal viscosities will be different for different applications.
  • the desired viscosity for any given formulation or use may vary, for example, according to the preference of the physician, the manner of application and type of applicator used, the amount of formulation needed, the area to which the formulation is to be applied, and similar considerations.
  • the invention is directed to a method of treating neurological disorder in particular for the treatment of Ataxia.
  • at least 90% of the liquid droplet size is more than 10 microns in order to prevent the inhalation of glucocorticoid into the lungs.
  • the present invention delivers and releases medicament in the form of small droplets, co-administration of water is not required thus making the oral spray formulation highly suitable for pediatric and geriatric patients who need frequent or immediate medical intervention.
  • the oral spray composition can be sprayed over the tongue by using a metered dose spray pump that will deliver a composition preferably between the ranges of from about 40 microliters to about 350 microliters.
  • the daily dose of active ingredient can administered as a single dose.
  • the dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors, including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, pharmacological considerations, half-life of the drug, and eventual concomitant therapy with other drugs. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state.
  • Spray systems are particularly useful for delivering therapeutics to the upper alimentary canal. Suitable spray delivery systems include both pressurized and non-pressurized (pump actuated) delivery devices.
  • the glucocorticoid steroid(s) containing solution, delivered as an oral spray, is preferably an aqueous solution; however, organic and inorganic components, emulsifiers, excipients, and agents that enhance the organoleptic properties (i.e., flavoring agents or odorants) may be included.
  • the solution may contain a preservative that prevents microbial growth (i.e., sodium benzoate).
  • compositions of this invention preferably contain from about 1-95% v/v and, most preferably, about 5-50% v/v, of the co-solvent.
  • the spray delivery system is normally designed to deliver from about 40 to about 350 microliters per actuation, and therapy may require from about 1 to about 10 actuations per dose.
  • the rheological properties of the spray formulation are optimized to allow shear and atomization for droplet formation.
  • the spray delivery device is designed to create a droplet size which promotes retention on mucosal surfaces of the upper alimentary canal and minimize respiratory exposure.
  • the present invention preferably minimizes the errors related to dosing accuracy of solutions delivered by an oral dropper device. Dose accuracy is critical to therapeutic efficacy when delivering small volumes and large volumes of oral liquids for in children. Ease of administration, increased compliance for patients who have difficulty swallowing solid oral dosage forms and large volumes of liquid formulation.
  • the formulations of the invention preferably have the advantage of permitting dose titration, should this be desired based on patient weight and minimize errors related to the accuracy of dosing when compared to marketed devices e.g. oral droppers.
  • the stable liquid pharmaceutical formulation of the present invention is an oral spray formulation that is used to treat a neurological disorder or disease in mammals (humans), such as ataxia.
  • a neurological disorder or disease in mammals such as ataxia.
  • mammals humans
  • administration of an oral liquid dose of glucocorticoid requires the patient to swallow a significant volume of liquid.
  • the stable oral formulations allow for the reduction of liquid volume from about 15-20 ml for a unit dose to a fraction of that, i.e., from about 1 to about 5 sprays (e.g., each spray about 0.14 ml) of a unit dose of an aqueous solution of the disodium phosphate salt of betamethasone.
  • the stable oral liquid formulation has a concentration of the disodium salt of the glucocorticoid from about 0.25 mg/ml to about 12 mg/ml, wherein each spray has a liquid volume from about 0.040 ml to about 0.350 ml and the unit dose is delivered in from about 1 to about 20 sprays. In certain preferred embodiments, each spray has a liquid volume from about 0.040 ml to about 0.350 ml, and preferably about 0.14 ml.
  • the glucocorticoid is the disodium phosphate salt of betamethasone and each spray has a liquid volume of about 0.14 ml
  • the dose of betamethasone is delivered to the human patient in e.g., from about 1 to about 5 sprays.
  • the concentration of the solubilized glucocorticoid is preferably from about 0.33 mg/0.14 ml to about 1.32 mg/0.14 ml, or to about 1.65 mg/0.14 ml.
  • oral spray formulations of the present invention are also particularly useful in asthmatic patients.
  • the dose of betamethasone is titrated until steady-state is achieved.
  • the dose of the oral betamethasone spray formulation during a titration phase is from about 0.01 to about 0.2 mg/kg patient body weight administered once over a 12 hour and or 24 hour period. This translates to a betamethasone dose from about 0.07 mg to about 28 mg total per day, based on an average adult weighing 70 kg (based on betamethasone base).
  • the betamethasone dose may be from about 0.07 mg to about 14 mg for once daily dosing (every 24 hours) and from about 0.14 mg to about 28 mg for twice-a-day dosing (every 12 hours), based on an average adult weighing 70 kg (based on betamethasone base).
  • the titration period may be, e.g., from about 2 to about 4 weeks, until steady-state is achieved.
  • the dose can be further titrated based on the individual patient response.
  • the dose of the oral betamethasone spray formulation at steady-state in such embodiments is preferably from about 0.02 to about 0.1 mg/kg patient body weight administered once over a 12 hour and or 24 hour period.
  • glucocorticoid is easily adjustable depending on the choice of particular glucocorticoid.
  • glucocorticoid based on betamethasone
  • a person having ordinary skill in the art would use the above information to calculate equivalent doses of one of the other (preferred) glucocorticoids if another glucocorticoid is to be administered to the patient.
  • the oral spray formulation of the present invention provides droplets that are greater in size than 5 microns, and in preferred embodiments no more than about 10% of the droplets should be below 10 microns in diameter. In certain preferred embodiments of the invention, not more than about 0.5% of the droplets are below 10 microns in diameter.
  • a betamethasone liquid formulation is prepared using the ingredients set forth in Table 1.
  • the formulation is prepared as follows: Add betamethasone to purified water while stirring and mix till a clear solution is observed. Add preservative, buffering agent and other excipients while stirring and mix for 30 minutes till a clear solution is formed. Store the solution in a glass bottle with cap or metered dose mechanical pump.
  • Example 1 has the advantage of permitting dose titration, should this be desired, based on the patient weight.
  • An added advantage is that the volume of solution administered to achieve therapeutic efficacy is less than 1 ml, which can administer with great accuracy using a metered dose pump spray.
  • Each spray contains 1.32 mg of betamethasone sodium phosphate and a total volume of 0.14 ml.
  • Example 1 The oral spray droplet size distribution of Example 1 is set forth in Table 2 and FIG. 1 (average droplet size distribution plot of Example 1).
  • Table 3 below provides the number of sprays required every 12 hours based on the patient's body weight for the formulation of Example 1.
  • a betamethasone liquid spray formulation is prepared using the ingredients set forth in Table 4.
  • Example 3 Composition mg/spray mg/spray Glucocorticoid 0.66 0.33 (betamethasone disodium phosphate) Citric acid 0.60 0.60 Sorbitol 6.00 6.00 Sodium benzoate 0.18 0.18 Flavor 0.24 0.24 Purified Water Qs Qs The formulation is prepared as follows: Add glucocorticoid steroid in purified water while stirring and mix till a clear solution is observed. Add preservative, buffering agent and other excipients while stirring and mix for 30 minutes till a clear solution is formed. Store the solution in a glass bottle with cap or metered dose mechanical pump.
  • Examples 4 and 4b are dry mixes for reconstitution (as is or lyophilized). The ingredients are set forth in Table 5 below.
  • the xanthan gum is Example 4b is included as a thickening agent.
  • a betamethasone oral syrup formulation is prepared using the ingredients set forth in Table 6 below.
  • the formulation is prepared as follows: Add betamethasone to purified water while stirring and add sorbitol and mix until a syrup is formed. Add preservative, buffering agent and other excipients while stirring and mix for 30 minutes till a clear solution is formed. Store the solution in a glass bottle with cap.
  • the present oral spray invention reduces dose volume administered every twelve hours by more than 90 volume percentage (Table 7) thus facilitating ease of use and compliance by the pediatric AT patient who find it difficult to swallow large volumes of liquid.
  • Example 1 The formulation of Example 1, 2 and 3 was filled in the 5 ml amber glass bottles with screw cap closure and subjected to stability studies under the following conditions:
  • Samples were analyzed to measure the percentage of betamethasone base conversion in the formulation at different temperatures over time. Also physical stability of the invented formulation example, precipitation of betamethasone in solution and pH drift was recorded.
  • Betamethasone oral spray (betamethasone sodium phosphate 1.32 mg per 0.14 ml spray) 40° C. ⁇ 2° C./75% RH ⁇ 5% 25° C. ⁇ 2° C./ RH 60% RH ⁇ 5% RH
  • Assay % Betamethasone ⁇ LOQ 4.56 6.96 >10 — 0.45 ⁇ LOQ ⁇ LOQ base, Area % Total ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ — ⁇ LOQ ⁇ LOQ impurities, % Physical Stable Stable Stable Not Not Stable Stable Stable Stable stability stable Stable 25° C.
  • Betamethasone oral spray (betamethasone sodium phosphate 0.66 mg per 0.14 ml spray) 40° C. ⁇ 2° C./75% RH ⁇ 5% 25° C. ⁇ 2° C./ RH 60% RH ⁇ 5% RH
  • Betamethasone oral spray (betamethasone sodium phosphate 0.33 mg per 0.14 ml spray) 40° C. ⁇ 2° C./75% RH ⁇ 5% 25° C. ⁇ 2° C./ RH 60% RH ⁇ 5% RH
  • Initial 1 M 2 M 3 M 6 M 1 M 2 M 3 M Appearance Clear C C C — C C colorless solution Total 105.81 99.70 96.55 — 103.60 101.78 101.75 betamethasone, Assay % Betamethasone ⁇ LOQ 3.96 7.03 10.40 — 0.48 ⁇ LOQ 1.20 base, Area % Total ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ — ⁇ LOQ ⁇ LOQ ⁇ LOQ Impurities, % Physical Stable Stable Stable Stable Stable Not Stable Stable Stable Stable Stable stability Stable 25° C.
  • An in-vivo study was performed in healthy rabbits to evaluate drug release from a betamethasone oral spray made in accordance with Example 3.
  • a single dose crossover study to evaluate the pharmacokinetics and relative bioavailability of 0.25 mg betamethasone per spray (oral spray formulation), 0.14 ml per spray and 0.25 mg per 2 ml of betamethasone oral solution (equivalent to previously approved formulation).
  • the pharmacokinetics study was performed in 6 healthy rabbits (3 males and 3 females).
  • the reference product was a single 0.25 mg dose (2 ml) of betamethasone base administered orally with the help of oral gavage.
  • the test formulation was a betamethasone sodium phosphate 0.33 mg oral spray (equivalent to 0.25 mg betamethasone base and 0.1 mg/kg dose) administered as a single spray in the oral cavity (over the tongue) using a metered dose spray pump. Blood samples were collected at 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. All samples were analyzed using a validated analytical LC-MS method.
  • the mean C max was found to be 158.17 ng/mL at median T max of 2.0 hr.
  • the mean AUC 0-t and AUC 0-infinity was found to be 851.16 and 866.02 ng*hr/mL, respectively.
  • the mean elimination half-life was found to be 3.19 hr.
  • the clearance and volume of distribution were 5.30 mL/min and 1.77 L, respectively.
  • the relative bioavailability was found to be 121.13% relative to reference oral solution (equivalent to previously approved formulation).
  • the mean C max was found to be 82.63 ng/mL at median Tmax of 3.0 hr.
  • the AUC 0-t and AUC 0-infinity was found to be 709.29 and 729.40 ng*hr/mL, respectively.
  • the mean elimination half-life was found to be 3.93 hr.
  • the clearance and volume of distribution were 6.11 mL/min and 2.00 L, respectively.
  • Respective salt and base forms of betamethasone and dexamethasone were weighed and transferred in the glass test tube. Water was added in the test tube using micro pipet and mixed for 5 minutes using mechanical vortex and the solubility of the betamethasone was assessed. The results are presented in Table 12 below.
  • betamethasone base converted from the disodium phosphate salt when the aqueous oral spray formulation is stored at 25° C. up to 12 months on stability is reported in Table 13.
  • a linear regression statistical tool is used to predict the amount of betamethasone base formed over the drug product shelf life (24 and or 36 months). From the accelerated stability study data, we conclude that betamethasone base precipitates out in the oral spray formulation when it converts to more than 0.15 mg/0.14 ml (spray volume)(equivalent to 1.07 mg/ml).
  • Example 2 Example 3 months 1.32 mg/spray 0.66 mg/spray 0.33 mg/spray 0 0.000 0.000 0.000 1 0.006 0.004 0.002 6 0.028 0.014 0.007 9 0.042 0.021 0.011 12 0.063 0.030 0.015
  • Table 14 and FIG. 5 show the stability of different drug concentration per spray in oral spray formulation with respect to time using the linear regression statistical tool, when stored at 25° C.
  • Betamethasone base (in mg) converted at 25° C. at 12 and 24 months 24 months (Predicted value 12 months using linear regression) 0.33 0.015 0.029 0.66 0.030 0.058 1.32 0.063 0.120
  • aqueous oral spray formulation of betamethasone will be stable for 24 months as a clear solution at a concentration of up to 1.65 mg of betamethasone disodium phosphate per spray of 0.14 ml solution.
  • Dexamethasone liquid spray formulations are prepared using the ingredients set forth in Table 15.

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